The overall objective of the proposed studies is to gain significant insight into how the body's innate immune system responds to virus infections. This work is important because the innate immune system responds very early during infection and alerts other host defense components. Natural killer (NK) cells are best known for killing tumor cells but they have an important role in innate immunity against pathogens, such as cytomegalovirus (CMV), a major cause of morbidity and mortality, especially in immunocompromised human patients. In order to study NK cell responses to viruses, the applicant's laboratory has chosen to study murine CMV (MCMV) because CMV has species tropism. Nevertheless, MCMV recapitulates most features of human CMV infections, making it an important animal model. In prior work, the applicant's laboratory and collaborators identified Ly49H, an NK cell activation receptor, as responsible for genetic resistance to MCMV infection. In the previous funding period, the applicant's laboratory discovered that Ly49H specifically recognizes an MCMV-encoded molecule, termed m157, that appears to be structurally related to other putative, virus-encoded MHC class l-like molecules that may be involved in immune modulation. m157 expression triggers Ly49H-dependent target killing and cytokine production. In the genetic absence of Ly49h, anti-Ly49H treatment, or deletion of m157, infection is uncontrolled and early lethality ensues. However, in immunodeficient mice, m157 mutant viruses emerge, resulting in lethality at much later times, and indicating selection pressure from NK cells. However, some escape mutants have intact m157, suggesting they are escaping other innate immune components. In preliminary studies, the applicant's laboratory discovered that MCMV-infected cells appear early in the marginal zone of the spleen and have an unusual morphology. In addition, the investigators have produced new mice constitutively expressing a ligand for an NK cell activation receptor. These mice will be useful study NK cell tolerance. The specific aims of this renewal application are thus to study: 1) The interaction of NK cells with MCMV-infected cells in vivo;2) Immune modulation by MCMV;and 3) NK cell function in host expressing a ligand for an activation receptor. Therefore, these studies will provide significant insight into the molecular basis for host anti-viral defense in innate immunity.